We will relate risk factors for Alzheimer's Disease (AD) and dementia in the Framingham Offspring cohort and to Magnetic Resonance Imaging (MRI) and cognitive performance measures. Prospective epidemiological study of the Original Framingham cohort has been under way for 50 years. Dementia has been studied in this cohort since 1976, with 235 cases identified; 58 percent of these fulfilling criteria for AD. Their children, the Framingham Offspring, have been studied prospectively for 26 years. During this time, extensive risk factor data pertinent to AD and dementia have been collected, including: parental AD, apoE genotype, hypertension, stroke, stroke risk factors, post-menopausal estrogen therapy, nonsteroidal antiinflamatory drugs, education, and cigarette smoking. In short, a wealth of valuable prospectively collected data are available for the Offspring, e.g., 59 are apoE 4/4 homozygotes and 681 are apoE 3/4 heterozygotes. A neuropsychological test battery will be administered to the 3,000 Offspring, replicating the battery administered 22 years ago to their parents at a similar age. Quantitative MRI studies of white matter change, silent stroke and brain atrophy will be related to dementia risk factors and to cognitive performance. We hypothesize that the abnormalities detected by MRI scan and neuropsychological tests will be increased among participants with dementia risk factors. Of particular interest is the exploration of why some apoE4 carriers escape dementia and an examination of the interaction of risk factors with cognitive impairment. We will examine the genetic risk for AD and dementia. DNA has been collected on both the parents and offspring. A high density genome scan has been performed for a sample Framingham families and will soon be completed in the remainder. We will perform genetic linkage analyses for MRI and cognitive performance measures in order to identify regions of the genome containing genes predisposing to AD and dementia.